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Petros Grivas: Hello, I'm Petros Grivas. I'm a Physician at Seattle Cancer Care Alliance and an Associate Professor at the University of Washington, Fred Hutchinson Cancer Research Center. I am very excited and happy today to host my good friend and colleague, Dr. Arjun Balar, who is an Associate Professor at NYU in New York. He's also the Medical Director of the Clinical Trials Office there and also the Director of the GU Medical Oncology Program. Arjun welcome.

Arjun Balar: Thanks for having me.

Petros Grivas: Arjun, you have led a lot of work and efforts, especially with the KEYNOTE-057 trial in non-muscle invasive disease, specifically in patients with BCG unresponsive, non-muscle-invasive disease who cannot undergo radical cystectomy or refuse it; and you have presented in different symposium meetings, and now, hopefully, we will have the publication soon. I want to pick your brain about the pembrolizumab approval based on this great work. How do you see this being utilized in the real-world setting? How do you see the emerging data with some other drugs, intravesical delivered chemotherapy, or nadofaragene firadenovec, for example? And how is this going to play out in the real world, and any other comments you want to make of this?

Arjun Balar: Yes, Petros, I think when I kind of reflect back on the evolution of KEYNOTE-057, I think it reminds me of just how much we've learned, not just about bladder cancer biology, and how to approach treatment, but actually equally important, if not more important, is just how do patients perceive this disease? How do they perceive their treatment options, and what is it that they are looking for? And I think nothing is as more evident about that issue of patient perception, what they are looking for, than this particular study has really highlighted it. And what I mean by that is that for BCG unresponsive disease, and remember, BCG-unresponsive is finally a definition that we finally kind of felt comfortable arriving at in 2018, but we have always known it existed, which is essential for patients who are getting BCG installations, patients that have either CR and then relapsed or have outright refractory disease.

And then their options are really cystectomy or something, what we call salvage, which is not exactly a great word either, and patients know that cystectomy is highly curative. North of 90%, 95% percent of patients, depending on their initial NMIBC stage, will be cured of their disease if they undergo a cystectomy. That being said, though, cystectomy is highly morbid. Four, five percent rate of morbidity, I'm sorry, mortality, and about two-thirds of patients are hospitalized with some form of complications. So, there are a lot of issues related to this surgery that patients are desperate to avoid, so it was in this context that the FDA developed the guidance documentation in 2018.  A lot of thought leaders got together and said this is something that we need to work on, in comes immunotherapy with pembrolizumab and other agents.

Certainly, pembro is not alone in being tested in this population, but there was a clear need and rationale to test pembrolizumab in this setting. Again, high-grade CIS or papillary disease carries the same genomics that metastatic disease does, and we've seen activity in advanced disease, so it makes sense. Why not test in BCG unresponsive, and what we've learned... So KEYNOTE-057, as you mentioned, presented many times. Single-arm phase two study, you could even call it a phase three because we're allowed to do that in neurology trials sometimes. It's a phase two study focusing on CIS patients in cohort A, complete response rate at three months was the primary endpoint. And in the 96 efficacy evaluable patients that were eventually included in the FDA submission, we had a 41% CR rate at three months. Now I want to focus on that for a moment.

So the three-month CR rate, which is such an important endpoint because this trial actually was first developed in 2013, so that is actually a long history. And the FDA said, very clearly, treatment beyond persistence CIS was not permitted, so if patients did not have a CR at three months, they had to come off. So that means you cannot pass go past three months unless you had a CR. All right, so then the CR three to three months as a primary endpoint and duration of response and beyond that are key secondary endpoints. So 41% CR rate, about 57% of those CRs lasted 12 months or longer, and if you look at some of the landmark endpoints, you're looking at roughly 16, 17 patients that are having CRs that are lasting two years or longer out of the original 96 patients. What that translates to is give or take somewhere between 15% to 20% of patients having durable CRs that are lasting a long time.

So it begs the question, is that data sufficient for FDA approval? That's one question. Number two, is that data sufficient to warrant use in clinical practice? Do people feel comfortable with those data? And I think that is where we are learning, that I think, many of our colleagues in urology feel that that data is a little bit underwhelming. I would argue that this is a trial that was really well designed, three months of treatment, it's a hard stop. If it works, keep going, if it doesn't stop. You don't risk anything, and then continue on treatment, and there may be a subset of patients who avoid a cystectomy completely.

We did an additional analysis, which was to look at the rates of cystectomy, and are we delaying things unsafely? Thirty-eight patients underwent a cystectomy, eventually, as part of this trial. Only eight out of the 38, so that translates to 8%- I'm sorry, three out of the 38, so 8%, had upstaging to muscle-invasive disease or higher, and what it tells us is that if you look at a contemporary series of similar patients, the rate of upstaging is actually probably higher at 15%, so we know that we are not, unsafely, delaying cystectomy. 95%, 96% of the patients who enrolled in this trial were surgical candidates who just did not want the cystectomy. So the patients are showing us with their feet, what is it they are looking for? So I think this is a very attractive option. We just have to counsel our patients about their risks, and cystectomy is still curative. When patients are willing to accept that, that is what they need to be counseled about, but if they're not, then this is an effective option.

And the other agents are really exciting.  There is nadofaragene firadenovec which shows similar data. We saw some data for N-803 plus BCG as part of the QUILT-3 trial at GU ASCO 2021, similar responses, and duration of response. And frankly, I don't look at those drugs competing with each other. We are actually trying to compete with cystectomy. And so, in my view, all of these drugs are quite active, and I think they should be offered to patients in the appropriate setting.

Petros Grivas: Yes it does. You said patient advocates make the point that we need more options for the patients, and you made that point clear for the audience. The standard of care in BCG unresponsive high-risk non-muscle invasive disease is indeed radical cystectomy, with pelvic lymph node dissection.  The challenge you pointed out is that some people are not fit enough, either too frail to undergo that or they refuse despite long counseling. So having options, I think, is very important, and as you point out, there are many, many new options coming in and pembrolizumab now has FDA approval. Arjun, the last question for you is about biomarkers, and you have also done great work in the field. Do you have any, let's say favorite, or let's say some thoughts about how we can validate biomarkers now at all [inaudible 00:06:55] for patient selection with immunotherapy. I know it's a hard question.

Arjun Balar: Yes, that is a tough question. As far as immunotherapy-related biomarkers are concerned, I can tell you what isn't, and PD-L1 expression is not, and it's just been woefully inconsistent across trials. Even when we try to repeat or replicate the same experimental settings.  The best example is IMvigor 210 Cohort 1 versus IMvigor130, KEYNOTE-052 versus KEYNOTE-361. In both conditions, frontline included a similar patient population, same drug, same clone, wildly different outcomes as it relates to PD-L1 expression and opposite directions.  And so what I think it reminds us, is that trying to measure the immune system in a static way, when it is such a dynamic thing, and to measure PD-L1 expression in a static piece of tumor tissue to understand that it can vary, it's patchy and it's a dynamic process, it was proving to be very difficult.

And so, what I find probably the most useful as a biomarker for the use of immunotherapy, in particular, in the first line where it seems to be controversial, is good, old-fashioned clinical judgment, and that is why I call them clinical biomarkers, right? So they are not tissue. They are not genomic because I don't think we have anything that we can use genomically yet, but clinical biomarkers are performance statuses related to the disease, or is it related to patient protoplasm? Hemoglobin? What's the... Are their liver meds present? How sick and how extensive is the disease? Is it growing quickly? How symptomatic is the patient? All of those factors really can tell you which group of patients can safely be treated with immunotherapy, which patients need chemo, and which ones are kind of in-between, and I find that that is actually much more clinically useful than any biomarker so far.

Petros Grivas: It's interesting. You mentioned these factors, Arjun, actually, Dr. Ali Khaki, who is now at Stanford, and myself and others, did a retrospective study. We came up with a prognostic model, and we looked at things like performance status, liver mets, albumin, [inaudible] ratio. And we developed a prognostic model based on that in patients getting immunotherapy, which makes a point that sometimes, clinical factors can be relevant and, at least, give us some prognostic estimates. We are still struggling with predictive biomarkers, as you mentioned.  At the molecular level, [inaudible] validating predictive and molecular biomarkers. Arjun, I want to thank you for the great work in the field, number one. And secondly, for your time today. Looking forward to more discussions in the future, my friend.

Arjun Balar: My pleasure Petros, thanks for having me again.